Imprinting the location of an in-built RAFT agent and selective grafting of polymer chains inside or outside the pores of mesoporous silica nanoparticles

Journal Pre-proof Imprinting the location of an in-built RAFT agent and selective grafting of polymer chains inside or outside the pores of mesoporous silica nanoparticles Smrutirekha Mishra, Aditya Rawal, Leena Nebhani PII:

S1387-1811(19)30757-7

DOI:

https://doi.org/10.1016/j.micromeso.2019.109898

Reference:

MICMAT 109898

To appear in:

Microporous and Mesoporous Materials

Received Date: 5 September 2019 Revised Date:

3 November 2019

Accepted Date: 17 November 2019

Please cite this article as: S. Mishra, A. Rawal, L. Nebhani, Imprinting the location of an in-built RAFT agent and selective grafting of polymer chains inside or outside the pores of mesoporous silica nanoparticles, Microporous and Mesoporous Materials (2019), doi: https://doi.org/10.1016/ j.micromeso.2019.109898. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.

Imprinting the location of an in-built RAFT agent and selective grafting of polymer chains inside or outside the pores of mesoporous silica nanoparticles Smrutirekha Mishra,a Aditya Rawalb and Leena Nebhani*a Smrutirekha Mishra,a Prof. Leena Nebhani*a a Department of Materials Science and Engineering, Indian Institute of Technology Delhi, New Delhi-110016, India E-mail: [email protected] Dr. Aditya Rawalb b Mark Wainwright Analytical Centre and School of Chemistry, University of New South Wales, Sydney, NSW, 2052, Australia

Keywords: Organically modified silica, selective polymer grafting, RAFT polymerization, organic-inorganic hybrid, stimuli responsive polymer

Abstract Mesoporous silica nanoparticles (MSNs) primed with RAFT agent were synthesized via cocondensation of tetraethoxysilane (TEOS) and organoalkoxysilane RAFT agent. The nature of the R group in organoalkoxysilane based RAFT agent was varied in order to control the preferential location of polymer grafting. Two different RAFT agents were prepared, one RAFT agent contained phenyl ethyl as R group, and other RAFT agent contained isobutyric acid as R group. The stability of the organoalkoxysilane based RAFT agents was confirmed employing UV-Visible spectroscopy and

1

Succeeding

MSNs

this

RAFT

functionalized

H solution NMR spectroscopy techniques. preparation,

surface-initiated

RAFT

polymerization was carried out using N-isopropyl acrylamide (NIPAM). RAFT and polymer functionalized MSNs were then characterized by diverse techniques such as FT-IR, TGA, UVVisible spectroscopy, surface area measurement, X-ray photoelectron spectroscopy (XPS), 13

C and

29

Si solid-state NMR spectroscopy. The outcome of utilizing different types of

organoalkoxysilane RAFT agent on the morphology was examined using SEM and TEM analysis. Spherical and cuboid shape obtained for RAFT-COOH-MSNs and RAFT-Ph-MSNs respectively. Higher percentage of polymer grafting was observed in case of PNIPAM-COOHMSNs in comparison to PNIPAM-Ph-MSNs. The realization of preferential grafting of polymer on exterior or interior surface of RAFT MSNs was established using pore 1

size/volume analysis by BET as well as by XPS. The characteristic resonances in 13C and 29Si solid-state NMR and characteristic vibrations in FT-IR, confirms successful synthesis of organic-inorganic hybrids. The analysis of thermoresponsiveness of PNIPAM grafted MSNs was experimented by drug loading and release studies at different temperatures as well as by confocal laser scanning microscopy.

Introduction Elevated degree of organic functionalization[1] and its control in inorganic mesoporous silica nanoparticles (MSNs) [2] is a superlative inspiration and key motivation for Materials Scientists to mimic organic-inorganic [3] structures. In order to attain such structures, a particular regulation over the structure[4] and local placing [5] of the functional groups[6] are excessively required. The co-existence of organic functionalities in inorganic network renders MSNs many complimentary assets [7] and ability to be used in areas of catalysis[8], sensors [9], drug delivery [10] to name a few. MSNs furnishes a tunable platform for the inclusion of diverse range of organic functionalities covalently [11] appropriate to its indefinite amorphous walls [12], high surface area [13] and pore volume. [14] These organic functional groups can be subsumed [15] into MSNs by post-synthetic functionalization [16] method, in which the inorganic surface is functionalized/modified with the organic groups after the synthesis of the MSNs. However, in an another approach which is co-condensation

2

method, [17] the fusion of an organic group takes place during the synthesis of the porous silica inorganic network. The latter approach, also referred to as direct synthesis, has been the demanded route for most researchers as it renders easier functionalization with the advantage of a single pot synthesis [18] as well as better control of degree of functionalization with organic moiety.[19] The co-condensation method have been alluringly described by many researchers. [20][21][22] These articles have outlined the delicacy of cocondensation method as an immense confluent pathway for synthesis of organic-inorganic hybrid MSNs. They have discussed variety of organoalkoxysilanes, for example, based on alkyl-amino, alkyl-thiol and alkyl-phenyl moieties which have tendency to occupy the exterior and interior surfaces of the MSNs when MSNs are synthesized using cocondensation method. Consequently, to attain peculiar functionality and to confer desired properties certain parameters

needs

to

be

enormously

functionalization/modification,[21]

particle

improved, size,[22]

such

as

degree

morphology,[23]

of and

organic pore

structure.[24] Gazing to tune the organic functionality and morphology control[25] of MSNs, assorted parameters and conditions need to be pinned such as surfactant/silane molar ratios,[26] solvent,[27] temperature,[28] pH,[29] drying and stirring rates.[30] Other than these conditions one influential technique which gives a controllable location of the functional groups and morphology is “co-condensation method”. In the co-condensation technique, organic-inorganic hybrids are synthesized by synergetic approach at the micellewater interface between the organoalkoxysilane and the surfactant. Previously many researchers[31] have studied about the arrangement of the surfactant molecules and organoalkoxysilane precursor at the micellar-water interface. It is clearly demonstrated that when the hydrophobic hydrocarbon tails of the surfactant molecules come in contact with the hydrophobic organoalkoxysilane precursors they tend to reciprocate each other due to their hydrophobic-hydrophobic interactions and arranging itself to form long individual cylindrical micelles. Finally, after complete arrangement of micelles at Gouy-Chapman region, alkoxysilane group start to cross-link or condense out forming the MSNs network. Hence, by varying the hydrophobicity or hydrophilicity of the organoalkoxysilane as a structure-directing agent into the synthesis system it is possible to achieve the desired organic functionality either on the inner or on the outer of the MSNs.

3

The synthesis of organic-inorganic hybrid structure is highly dependent upon the nature and location of organic functionalities which would dictate control over the morphology and embrace its properties. Many times organic functionalized MSNs referred as periodic mesoporous organosilicas (PMOs)[32] derived from siloxanes containing organic group have shown important challenges and advances in different applications. Hunks et al. [33]reported about the challenges in the synthesis of PMOs. PMOs have countless advantage related to tuning of its in-built configuration starting from adjusting the organic moieties into the large amorphous wall of the silica network to modifying its shape, diversifying its mechanical, thermal and chemical properties. It was simultaneously reported that the thermal stability, mechanical support and enhanced hydrophobicity can be reformed by replacing the terminal hydroxyl group (-OH) in the siloxane network by organic groups within the network. Enumerating to the above points, silica network bridged with a carbon ligand would provide these siloxane network more stability towards hydrolysis and makes it easier for applying into diversified area. Furthermore, simply coating of these organic groups on the inorganic group would limit its usage due to easy removal upon scuffing. Hence it is an important challenge to modify the silica network with organic groups by chemical methods which would tune the hydrophobicity and porous network of the PMOs. Different application of these PMOs have been reported earlier by Ahadi et al. [34]where they developed a new catalyst based PMOs in which bipyridinium ionic liquid was supported on palladium (Pd). It was reported that due to the stabilized Pd within the pores of MSNs it was possible to achieve enhanced catalytic behaviour for Suzuki–Miyaura coupling reactions in water with high efficiency. Lin et al.[31] studied series of organic group (nitrile, isocyanate, primary, amine, secondary, urea and vinyl) which were co-condensed with TEOS leading to the formation of an organicinorganic hybrids. In this case, different types of particle shapes such as rods, spheres and tubes shaped MSNs were synthesized by tuning the hydrophobicity and hydrophilicity of the organoalkoxysilane precursors. Likewise, Zhang et al.[35] detailed the possibilities to prepare different types of morphologies such as spheres and rods by differing the types of silanes by co-condensation method. They also showed that only morphology can be controlled but particle size can also be varied by this method. More work on MSNs is reported by Stein[36], Mann[37], Macquarrie[38] and Stucky[39] via co-condensation by

4

varying type of functionality such as alkyl, vinyl, thiol and aromatic groups. The important challenge for grafting any polymer from the inorganic surface relies on the capability of the surface to achieve maximum functionalization. Previously all the methods that have been reported are based upon post-modification of MSNs with the RAFT agent, followed by polymer grafting. Our ideology for using the organoalkoxysilane RAFT agent via cocondensation approach allows functionalization of RAFT groups in higher amount into the MSNs and thus preferentially more polymeric chains would be grafted on the surface. In addition, by post-modification techniques only outer surface can be grafted/modified with polymer, however, co-condensation approach provides a handle to preferentially modify outer or inner surface of MSNs Till date, co-condensation method has been utilized widely for the synthesis of organic-inorganic hybrid [40][41] using different types of organoalkoxysilanes, but not using organoalkoxysilane based RAFT agent. Herein, we report for the first time ability to tune the morphology as well location for preferential polymer grafting by changing the nature of R group of an organoalkoxysilane based RAFT agent. The MSNs of varying morphology were prepared using two different organoalkoxysilane based RAFT agents in the existence of CTAB as a template via cocondensation, finally resulting in RAFT primes MSNs (Scheme 1). The two different organoalkoxysilane used in this work are referred to as RAFT-Ph (containing phenyl ethyl as R group) and the second organoalkoxysilane referred to as RAFT-COOH (containing isobutyric acid as R group). After thorough analysis these RAFT-MSNs were further used for grafting of NIPAM via a surface-initiated RAFT polymerization. Preferential location of grafting for PNIPAM is controlled through the nature of RAFT agent. In case of MSNs primed with RAFT-Ph, preferential polymer grafting occurs inside the pores while in the case of MSNs primed with RAFT-COOH preferential polymer grafting takes place outside the pores. The thermally responsive nature of prepared PNIPAM-MSNs was further exploited for its use in drug-carrying capability at varying temperatures.

Experimental Preparation and stability of organoalkoxysilane RAFT agent containing isobutyric acid as R group. (RAFT-COOH) and organoalkoxysilane RAFT agent containing phenyl ethyl as R group (RAFT-Ph) 5

Synthesis and stability of RAFT agent containing isobutyric acid as R group is discussed in the supporting information. Synthesis and stability of organoalkoxysilane RAFT agent containing phenyl ethyl as R group is discussed on our previous work. [19] Preparation of RAFT-COOH-MSNs and RAFT-Ph-MSNs TEOS (44.8 mmol) and RAFT agent (5.8 mmol) was added to solution of CTAB (5.5 mmol) in water (480 mL) containing 2M NaOH (14 mmol). The solution was heated at 80°C for 2h. The RAFT agent primed MSNs were collected by centrifugation. The RAFT agent primed MSNs were washed several times with ethanol and water followed by vacuum drying for 24 h The mesoporous structure was obtained by removal of template using solvent extraction method. The control-MSNs were prepared in the same manner, the procedure for the preparation of control-MSNs is discussed in the Supporting Information. Kinetics of RAFT polymerization of NIPAM on RAFT-COOH-MSNs and RAFT-Ph-MSNs To determine the controlled nature of both the RAFT agents, kinetic studies on RAFT polymerization for the growth of PNIPAM chains from RAFT-COOH-MSNs or RAFT-Ph-MSNs were conducted. The evolution of molecular weight with respect to time is discussed in Table 1. RAFT polymerization of NIPAM (10 g) was carried out in DMF (30 mL) using AIBN (10 mg) at 65°C for 5, 10, 24 and 36 h. After the required time duration, the polymer grafted MSNs were washed several times with THF, followed by drying under vacuum for 24h. Determination of molecular weight by aminolysis 50 mg of PNIPAM-COOH-MSNs or PNIPAM-Ph-MSNs were added to 20 mL of THF containing 20 mg of triphenylphosphine. Further 2.5 mL of n-hexylamine was added and the solution was stirred overnight at the room temperature under nitrogen atmosphere. Finally MSNs were extracted by centrifugation and subjected to TGA. The supernatant THF solution was collected, concentrated and subjected to SEC analysis. Loading of doxorubicin into control-MSNs and polymer functionalized MSNs Loading of doxorubicin was performed using control-MSNs, PNIPAM-COOH-MSNs and PNIPAM-Ph-MSNs by dispersing individual samples in PBS (pH 7.4) solution of 4 μM doxorubicin. The doxorubicin loaded samples were stirred at 25°C and 40°C for 24h. Finally, the doxorubicin loaded control-MSNs, PNIPAM-COOH-MSNs and PNIPAM-Ph-MSNs were washed several times with water followed by drying under vacuum for 24 h. The content of doxorubicin that is entrapped in the pores of the MSNs was calculated before and after at

6

25°C and 40°C by measuring the concentration of the supernatant solution at a wavelength of 485 nm by UV-Visible spectroscopy. The loading efficiency for PNIPAM-COOH-MSNs and PNIPAM-Ph-MSNs was calculated by the following equation:

where, LE is the loading efficiency, [Dox]s is the amount of Doxorubicin in supernatant buffer solution and [Dox] is the total initial content of Doxorubicin (mmol/g). Procedure for release of doxorubicin from polymer functionalized MSNs To analyse the release of doxorubicin from the individual samples; the initial doxorubicin loaded samples were re-dispersed in PBS (pH 7.4) and stirred at 20°C, 30°C, 40°C for 24 h. In order to evaluate the amount of doxorubicin released from the pores of the samples, supernatant solutions concentration was determined initially and finally (as well as at varying time interval) by recording absorption at 483 nm using UV-Visible spectroscopy. The release efficiency (RE) for PNIPAM-COOH-MSNs and PNIPAM-Ph-MSNs was calculated using following equation:

where, [Dox]I is the initial content of doxorubicin in the PNIPAM-MSNs and [Dox]r is the content of doxorubicin that is released from the MSNs into the PBS solution (mmol/g).

Scheme 1. Schematic representation for co-condensation of organoalkoxysilane RAFT agent based on isobutyric acid as R group and phenyl ethyl as R group with TEOS leading to the 7

formation of RAFT-COOH-MSNs and RAFT-Ph-MSNs. Further, RAFT-COOH-MSNs and RAFTPh-MSNs were functionalized with PNIPAM using RAFT polymerization producing PNIPAMCOOH-MSNs and PNIPAM-Ph-MSNs.

Results and Discussion In the present work, we are reporting for the first time ability to control morphology as well as preferential location for polymer grafting by varying the nature of RAFT agent used during the synthesis of MSNs. In the current approach, co-condensation of TEOS with two different types of organoalkoxysilane RAFT agent in the presence of low concentration of CTAB in an aqueous basic medium was achieved. In order to synthesize RAFT agent primed MSNs, it was necessary to successfully synthesize RAFT agent based isobutyric acid and phenyl ethyl moiety as R group. The RAFT agents were synthesized by the reaction of 3mercaptopropyltriethoxysilane and 2-bromoisobutyric acid in the presence of carbon disulphide for the synthesis of RAFT agent containing isobutyric acid as R group (RAFTCOOH) (Supporting Information Figure S1 and S2) and 1-bromoethylbenzene was used for the synthesis of RAFT agent containing phenyl ethyl as R group (RAFT-Ph-MSNs). The organoalkoxysilane RAFT agent containing phenyl ethyl as R group has been previously reported by our group and has been used for the synthesis of RAFT agent functionalized MSNs as well as PNIPAM functionalized MSNs [19]. The stability for both the RAFT agents utilized for the synthesis of RAFT agent primed MSNs in the presence of NaOH and HCl was confirmed

by

1

H,

13

C

NMR

and

UV–Visible

spectroscopies.

The

stability

of

organoalkoxysilane based RAFT agent containing phenylethyl as R group has been reported previously.[19] The main comparison of

1

H NMR and UV-Visible spectra of

organoalkoxysilane based RAFT agent containing isobutyric acid as R group, before and after its reactions with NaOH and HCl respectively are shown in Figure S3. Establishing the 1H NMR results, it was concluded that both the RAFT agents used for co-condensation with TEOS were stable during the synthesis of MSNs. After establishing the stability of RAFT agents based on COOH and Ph group, both organoalkoxysilane RAFT agents were utilized for the synthesis of RAFT agent primed MSNs (RAFT-COOH-MSNs and RAFT-Ph-MSNs). The prepared RAFT MSNs were further utilized for

8

controlled radical polymerization of NIPAM via “grafting-from" approach resulting in PNIPAM-COOH-MSNs and PNIPAM-Ph-MSNs. All the MSNs, RAFT-COOH-MSNs, RAFT-Ph-MSNs and PNIPAM-COOH-MSNs, PNIPAM-PhMSNs were characterized using variety of techniques, which actively indicates that RAFTCOOH-MSNs displayed functionality of RAFT agent mostly on exterior surface of the mesoporous silica leading to spherical shaped nanoparticles, while RAFT-Ph-MSNs exhibited functionality of RAFT agent mostly in the interior surface resulting in the cuboid structured mesoporous nanoparticles, which finally controls the growth of PNIPAM chains on exterior and interior surfaces of the MSNs respectively. The morphology of RAFT-COOH-MSNs, RAFTPh-MSNs, PNIPAM-COOH-MSNs, and PNIPAM-Ph-MSNs is discussed in detail in later sections of this manuscript. The FT-IR spectra of the control-MSNs, RAFT-COOH-MSNs and PNIPAM-COOH-MSNs are shown in Figure 1 (a). The bands around 3391 cm−1, 1099 cm−1, and 804 cm−1 were observed in the FT-IR spectra of RAFT-COOH-MSNs and PNIPAM-COOH-MSNs. These bands can be assigned to O-H stretching bands, asymmetric stretching vibration band of Si-O-Si and Si-OSi symmetric stretching vibrations respectively. In the FT-IR spectra for RAFT-COOH-MSNs additional absorption bands (as compared to control-MSNs) were observed at 2922 cm−1 and 1712 cm−1 which are due to C-H stretching vibration and C=O stretching vibration of the carboxylic group. In the PNIPAM-COOH-MSNs, a small band at 1523 cm-1 was observed indicating the secondary amide group from the PNIPAM chains.

Figure 1. a) FT-IR spectra for control-MSNs, RAFT-COOH-MSNs, PNIPAM-COOH-MSNs having the characteristic bands at 1099 cm−1 (Si-O-Si asymmetric vibration), 1712 cm-1 (C=O

9

stretching), 2922 cm-1 (C-H stretching) and 1523 cm-1 (secondary amide) respectively; b) FTIR spectra for control-MSNs, RAFT-Ph-MSNs, PNIPAM-Ph-MSNs having the characteristics bands at 1095 cm-1 (Si-O-Si asymmetric vibration), 2914 cm-1 (C-H stretching) and 1524 cm-1 (secondary amide).

Similarly, FT-IR spectra of the control-MSNs, RAFT-Ph-MSNs, PNIPAM-Ph-MSNs is shown in Figure 1 (b). In the FT-IR spectra of RAFT-Ph-MSNs and PNIPAM-Ph-MSNs, bands were observed around 3400 cm−1, 1095 cm−1, and 806 cm−1 which are also assigned to O-H stretching bands, asymmetric stretching vibration band of Si-O-Si and Si-O-Si symmetric stretching vibrations respectively. In the PNIPAM-Ph-MSNs, a sharp band at 1524 cm-1 was observed which indicates the secondary amide group of the PNIPAM chains. Based on these results, FT-IR analysis confirms successful functionalization of MSNs with RAFT agent as well as polymer chains. In addition to other techniques, UV-Visible spectroscopy was used to confirm the cocondensation of organoalkoxysilane RAFT agent with TEOS. Considering the UV-Visible spectra for control-MSNs, RAFT-COOH, RAFT-COOH-MSNs, PNIPAM-COOH-MSNs, RAFT-Ph, RAFT-Ph-MSNs, and PNIPAM-Ph-MSNs as shown in Figure S4; the absorption from the thiocarbonyl group around 310–332 nm is due to the allowed π-π* transition which in turn gives a clear indication that trithiocarbonate group is retained after the co-condensation as well as polymerization. TGA was performed on organoalkoxysilane based RAFT agent functionalized MSNs as well as polymer grafted MSNs for which the polymerization time was 36 h. The weight loss obtained for control-MSNs, RAFT-COOH-MSNs, and PNIPAM-COOH-MSNs is shown in Figure 2(a). The control-MSNs showed a weight loss of 8.7 wt.%, which is due to the removal of adsorbed water as well as dehydration of surface hydroxyl groups. In the case of RAFTCOOH-MSNs, the total weight loss was 26.8 wt.%, with a first stage weight loss 6.4 wt.%, and the second stage weight loss of 20.4 wt.%. After NIPAM polymerization, the total weight loss was 52.1 wt.%. First weight loss of 2.4 wt.% was observed and second weight loss of 49.9 wt.%. Similarly, weight loss for control-MSNs, RAFT-Ph-MSNs, and PNIPAM-Ph-MSNs is shown in Figure 2(b). In the case of RAFT-Ph-MSNs, the total weight loss was 25.9 wt.%, with a first stage weight loss of 6.6 wt.%, and the second stage weight loss of 19.3 wt.%. After

10

NIPAM polymerization, the total weight loss was 33.3 wt.%. The first weight loss of 8.2 wt.%, the second weight loss of 24.8 wt.%. The contrastingly higher weight loss for PNIPAM-COOH-MSNs as compared to PNIPAM-PhMSNs indicates that in the case of RAFT-COOH MSNs, the trithiocarbonate groups are easily accessible by monomers and hence are present preferentially on the outer surface of MSNs, leading to higher amount of grafting of the PNIPAM chains. While in the case of PNIPAM-PhMSNs, lower weight loss was observed, indicating that in the case of RAFT-Ph-MSNs, the trithiocarbonate group are not easily accessed by monomer and hence located inside the pores of MSNs, this is due to the interaction between phenyl ethyl group of the RAFT agent and alkyl chains of CTAB leading to significantly lower amount of polymer chains grafting. Table S1 in the Supporting Information shows detailed weight loss in different steps of the degradation.

Figure 2. a) Weight loss for control-MSNs, RAFT-COOH functionalized MSNs, and PNIPAMCOOH-MSNs. The total weight loss for PNIPAM-COOH-MSNs was around 52.1 wt.% which is higher than weight loss for RAFT-COOH-MSNs (26.8 wt.%) and control-MSNs (8.7 wt.%). b) Weight loss for control-MSNs, RAFT-Ph-MSNs, and PNIPAM-Ph-MSNs. Total weight loss of 33.3 wt.% for PNIPAM-Ph-MSNs higher than weight loss for RAFT-Ph-MSNs (25.9 wt.%).

In order to understand the surface initiated RAFT polymerization, kinetics studies were performed at different time period (5, 10, 24 and 36 h). The molecular weight for PNIPAM grafted on RAFT-COOH-MSNs and RAFT-Ph-MSNs were determined using size exclusion chromatography after an aminolysis experiment using excess of primary amine which results in cleavage of polymer chains grafted from MSNs. The number and weight average 11

molecular weight was obtained at different time period is shown in Table 1. The MSNs grafted with polymer chains with 36 h polymerization time were analysed after performing aminolysis with SEC as well TGA was performed for MSNs after cleaving the polymer chains. As shown in Figure S5, the TGA of PNIPAM-COOH-MSNs before aminolysis shows a weight loss of 52.1 wt.% while PNIPAM-COOH-MSNs analysed after aminolysis showed a weight loss of 29.7 wt.%. Similarly, PNIPAM-Ph-MSNs before aminolysis showed a weight loss of 33.3 wt.% while PNIPAM-Ph-MSNs after aminolysis showed a weight loss of 28.6 wt.%. This indicates that majority of polymer chains are cleaved from the MSNs by performing aminolysis.

Table 1. Molecular weight of PNIPAM at different time interval of polymerization by surface initiated RAFT polymerization PNIPAM-COOH-MSNs Time (h) 5

(g/mol) 950

(g/mol) 1300

10

2780

24 36

PNIPAM-Ph-MSNs PDI

Based upon the

1.2

Time (h) 5

(g/mol) 890

(g/mol) 1260

PDI 1.2

3250

1.17

10

1620

2070

1.2

4270

4700

1.10

24

2380

2960

1.18

5680

6370

1.12

36

3620

4520

1.16

of the polymeric chains cleaved from the surface and the percent

weight loss determined by TGA, grafting ratios were calculated by using equations given in the Supporting Information, where Gr1 is the mass ratio of the functionalized RAFT agent and Gr2 is the molar ratio of RAFT agent on MSNs and Gp1 is the mass ratio of the polymer grafted from MSNs while Gp2 is the molar ratio of polymer grafted from MSNs.[42][43] W%Control-MSNs, W%RAFT-MSNs and W%PNIPAM-MSNs are the % weight loss from TGA due to water, RAFT functionality and grafted polymeric chain from room temperature to 750°C. Gp1, Gp2 is calculated for MSNs in which the polymerization time was 36 h and is tabulated in Table 2. As compared to literature report [42], this method of polymer grafting leads to higher grafting. Considering complete utilization of the organoalkoxysilane based RAFT agent during the co-condensation process, 23.4% grafting of organoalkoxysilane based RAFT agent should be obtained for RAFT-COOH MSNs as compared to 16.1% observed 12

experimentally using TGA. Similarly, for RAFT-Ph-MSNs, grafting of 24.4% should be obtained based on mass of initial organoalkoxysilane based RAFT agent introduced as compared to 14.4% observed experimentally. Table 2. Grafting ratio for both organoalkoxysilane RAFT agent and polymer on the surface of MSNs. Sample

Gr1 (%)

Gr2 (umol/g)

Gp1 (%)

Gp2 (umol/g)

RAFT-COOH-MSNs

16.1

401.8

-

-

PNIPAM-COOH-MSNs

-

-

73.0

130.2

RAFT-Ph-MSNs

14.4

343.7

-

-

PNIPAM-Ph-MSNs

-

-

9.06

25.0

A good observation for the organoalkoxysilane RAFT agent on the morphology of the prepared co-condensed MSNs (RAFT-COOH-MSNs, RAFT-Ph-MSNs) and PNIPAM grafted MSNs (PNIPAM-COOH-MSNs, PNIPAM-Ph-MSNs) was studied using SEM, TEM, and surface area analysis. By the usage of BET and BJH analysis the surface area and pore size distribution was calculated.[44] The morphology of the MSNs [23] is controlled by many factors other than ratio and type of organoalkoxysilane used. For the system described in this manuscript, having organoalkoxysilane RAFT agent possessing different R groups (Scheme 1), the interaction of its R group, with hydrocarbon tails of CTAB credibly lead to the formation of particles of different morphology. In the case of RAFT agent containing COOH in the R group, spherical morphology was observed while in the case of RAFT agent containing phenylethyl in the R group, a cuboid type morphology was observed. The SEM of RAFT-COOH-MSNs, PNIPAM-COOH-MSNs, RAFT-Ph-MSNs, and PNIPAM-Ph-MSNs is shown in Figure 3 and Figure 4. The SEM and TEM of control-MSNs is shown in Figure S6 in the Supporting Information. From the TEM micrographs as shown in Figure 3 and Figure 4, mesoporous structure can be observed in organoalkoxysilane based RAFT agent functionalized MSNs as well as polymer functionalized MSNs [45-46]. The SEM and TEM of control-MSNs is shown in Figure S10 in the supporting information. The magnified SEM and TEM images for RAFT-COOH-MSNs and RAFT-Ph-MSNs are shown in Figure S7 and S8 in the supporting information.

13

The hypothesis behind different morphology is justified by the interaction of R group present in the organoalkoxysilane based RAFT agent and templating agent (CTAB). As depicted in Scheme 2, initially CTAB arranges itself into a micellar structure on coming in contact with water, with hydrophilic tetraalkyl ammonium groups projected outwards and hydrophobic alkyl chains projected inwards.

Figure 3. SEM and TEM micrographs for (a) organoalkoxysilane based RAFT agent functionalized MSNs (RAFT-COOH-MSNs) with spherical morphology and (b) PNIPAM grafted MSNs from RAFT-COOH-MSNs.

14

Figure 4. SEM and TEM micrographs for (a) organoalkoxysilane based RAFT agent functionalized MSNs (RAFT-Ph-MSNs) with cuboid morphology and (b) PNIPAM grafted MSNs from RAFT-Ph-MSNs.

When the RAFT agent containing phenyl ethyl as R group comes in the contact with this micellar structure adapted by CTAB in water, the R group interacts more with hydrophobic part of micellar structure. This results in the formation of intercalated layers and thus distorting its shape for complete spherical to cuboid. In turn, by this interaction of phenyl ethyl group of organoalkoxysilane with the CTAB, the accessibility to trithiocarbonate group in the case of RAFT-Ph-MSNs is restricted, this has been reported in our previous wok.[19] This in contrast to organoalkoxysilane RAFT agent containing COOH in the R group. In this case, the hydrophilic part inhibits the formation of long micelle without intercalating layers and it tries to condense more on the outwards of the micellar structure. Thus, maintaining the shape as spherical as shown in Scheme 2. Finally at the surface of the micelles [45] tetraethoxysilane and siloxy group of the RAFT agent co-condenses with each other giving a cross-linked spherical or cuboid shaped particles.

15

Scheme 2. Mechanism of the interaction of the organoalkoxysilane based RAFT agent containing isobutyric acid as R group with templating agent leading to the formation of spherical shape

In the case of RAFT agent containing isobutyric acid as R group, spherical morphology was observed with a surface area of 414 m2/g for RAFT-COOH-MSNs and 362 m2/g for PNIPAMCOOH-MSNs while in the case of RAFT agent containing phenylethyl in the R group, a cuboid type morphology was observed with surface area of 781 m2/g for RAFT-Ph-MSNs and 692 m2/g for PNIPAM-Ph-MSNs. Therefore, in order to better understand porosity and volume before and after polymerization was studied. MSNs BET surface areas and BJH pore volumes and pore size distributions was calculated using nitrogen adsorption-desorption technique. As shown in Figure S9 and S10 in the Supporting Information, all the MSNs (RAFT-COOHMSNs, PNIPAM-COOH-MSNs, RAFT-Ph-MSNs, PNIPAM-Ph-MSNs) before and after the polymerization exhibited type IV BET isotherms consistent with the mesoporous structure[46]. The BET surface area, BJH pore size diameter and average pore volume is summarized in Table 3. The BET surface area, BJH average pore size and pore volume were varying depending on the nature of organoalkoxysilane and amount of polymer chains grafted.

16

Table 3. BET surface area, BJH pore size and pore volume of RAFT agent functionalized MSNs and PNIPAM grafted MSNs. BET surface area

BJH pore size

BJH pore volume

(m2/g)

(nm)

(cm3/g)

RAFT-Ph-MSNs

781

3.05

0.98

PNIPAM-Ph-MSNs

692

1.5

0.31

RAFT-COOH-MSNs

414

2.2

0.51

PNIPM-COOH-MSNs

362

2.3

0.58

Sample

The BJH pore size was changed from 3.05 nm for RAFT-Ph-MSNs to 1.5 nm for PNIPAM-PhMSNs while there is negligible change in pore size of PNIPAM-COOH-MSNs. In the case of RAFT-COOH-MSNs the pore size was 2.2 nm and for PNIPAM-COOH-MSNs the pore size was 2.3 nm. These results also suggest that as PNIPAM-Ph-MSNs is showing smaller pore size than RAFT-Ph-MSNs, in this case the pores are filled with polymeric chains. Such observations from BJH experiments indicates that as per the hypothesis the PNIPAM is mostly on the interior surface of the pores for RAFT-Ph-MSNs and on the exterior surface for RAFT-COOH-MSNs. Therefore, in order to confirm the preferential location of RAFT agent and polymer grafting XPS experiment was performed. Figure S11 shows the XPS wide scan for control-MSNs. C1s signals which was observed can be due to the presence of carbonaceous substances in the trace quantity.[47] The peaks at 103 eV and 153.7 eV can be assigned to Si2p and Si2s from the control-MSNs surface. The XPS for RAFT-COOH-MSNs, PNIPAM-COOH-MSNs, RAFT-PhMSNs and PNIPAM-COOH-MSNs is shown in Figure 6. Considering Figure 6 (a) it can be clearly seen two new peaks at binding energies of 162 eV, 228 eV for RAFT-COOH-MSNs and 400 eV for PNIPAM-COOH-MSNs which can be assigned to S2p, S2s from the trithiocarbonate group of the RAFT agent and N1s from the PNIPAM chains. (Individual scan of each element are given in the Supporting Information Figure S12). Nevertheless, contrastingly different results were observed for RAFT-Ph-MSNs and PNIPAM-Ph-MSNs (Figure 6 (b)), in this case no binding energy for nitrogen is observed even after the polymerization of NIPAM.

17

Figure 6. (a) Wide scan for RAFT-COOH-MSNs and PNIPAM-COOH-MSNs and (b) Wide scan for RAFT-Ph-MSNs and PNIPAM-Ph-MSNs.

Therefore, it can be judged that the groups liable for detection on the surface of MSNs functionalized with RAFT agent containing COOH group shows prominent peak at binding energies corresponding to functional groups and polymeric chains. This in turn confirms that these functional groups and polymeric chains are grafted preferentially on the exterior surface of the pores. While in the case of RAFT agent containing phenyl ethyl group these elements are not detectable as they are not present on the surface. To confirm the co-condensation of organoalkoxysilane RAFT agent with TEOS as well as polymer functionalization of MSNs, solid state NMR was performed. As seen in Figure 7 (a), the 13C NMR spectrum of the control MSNs, shows a negligible signal, with only a small peak corresponding to the residual surfactant that was not removed by the extraction process. In comparison, the 13C NMR spectra of the RAFT functionalized MSNs (Figure 7 b and c) show multiple signals consistent with the signals of the RAFT-Ph-agent and RAFT-COOH-agent moieties. An overlay of the RAFT-only and PNIPAM-RAFT functionalized MSNs in Figures 7 (b) and (c), shows the extent of PNIPAM incorporation onto the MSNs. For the purpose of comparison, the 13C spectra of the MSNs have been scaled to the same intensity of peak “1” which corresponds to the directly bonded Si-C carbon of the RAFT agent. For the case of the RAFT-Ph-MSNs and PNIPAM-Ph-MSNs, the two spectra as virtually superimposable as seen in Figure 7 (b), indicating that the amount of PNIPAM grafted is very small. In comparison for the RAFT-COOH-MSNs and PNIPAM-COOH-MSNs, there is significant increase in the signal intensity clearly attributable to the grafting of PNIPAM. 18

Figure 7. 13C (a-c) and 29Si (d-f) solid state NMR of the control and functionalized MSNs. (a) and (d) are the

13

C and

29

Si NMR of the control MSNs respectively. Spectra (b) and (e)

plotted with thin lines are

13

C and

29

Si spectra of the RAFT-Ph-MSNs. Overlaid spectra

plotted in bold lines in (b) and (d) are the spectra of PNIPAM-Ph-MSNs. Spectra (c) and (f) plotted with thin lines are

13

C and

29

Si spectra of the RAFT-COOH-MSNs. overlaid spectra

plotted in bold lines in (c) and (f) are the spectra of PNIPAM-COOH-MSNs. Signal of the residual surfactant is labelled “R”. Peaks 1,2,3,13,14,15 and 16 in (b) correspond to the RAFT-Ph-MSNs, the peaks 1,2,3,5,6,7 correspond to the RAFT-COOH-MSNs in (c) and peaks 8,9,10,11,12 correspond to the PNIPAM in (c). The detailed assignment of the different carbon sites is presented in the Supporting Information Figure S13 for clarity. The

29

Si NMR provides further insight into the functionalization of the MSNs. The

29

Si

spectrum of the control MSNs only shows signals of Q2, Q3 and Q4 silicates, which is consistent with that expected for a high surface area mesoporous silica. In comparison, the RAFT functionalized MSNs show significant intensity of T2 and T3 silicate sites which is consistent with the formation of Si-C bonds in Q2 and Q3 silicates via functionalization with organoalkoxysilane based RAFT agent. For purpose of comparison, all the

29

Si spectra are

plotted to the same intensity of the Q3 site. A comparison between the 29Si spectra of the RAFT-Ph-MSNs and RAFT-COOH-MSNs indicates that there is a higher degree of T2 sites 19

formed on the RAFT-COOH-MSNs as compared to the RAFT-Ph-MSNs. While the possible mechanism for this effect is not clear, the T2 sites would be more accessible than the T3 sites and likely result in a greater degree of polymerization. This is consistent with the higher amount of PNIPAM grafting observed is in the PNIPAM-COOH-MSNs as compared to the PNIPAM-Ph-MSNs.

Figure 8. 13C {1H} and 29Si{1H) 2D HETCOR NMR of PNIPAM-COOH-MSNs. The 1D 13C and 29Si spectra are plotted on the top, while the 1D projections of the 1H dimension are plotted to the left in green and blue for the

13

C{1H} and

29

Si{1H} HETCOR’s respectively. Dashed

horizontal lines are guides to the eye.

Further evidence that the RAFT-COOH-MSNs is indeed functionalized by the PNIPAM is provided by a combination of 2D 13C{1H} and 29Si{1H} HETCOR NMR spectra as show in Figure 8. Here, the organic species, while the

29

13

C species show strong correlation peaks to alkyl and NH proton

Si species show a strong correlation signal to strongly adsorbed H2O

species, which are expected on the hydrophilic silica surface. Importantly there are significant intensities of cross-correlation peaks observed as well, for example, the relatively weaker correlation signal of the CH3 and CH2 protons is observed on the 29Si species, while the strong H2O signal is observed on the 13C species. These cross-correlation signals clearly demonstrate that the MSNs is extensively functionalized by the PNIPAM. PNIPAM is a well-known thermoresponsive polymer, it undergoes a reversible phase transition from a swollen hydrated state (below 32°C) to a collapsed dehydrated state (above 32°C). This temperature at which transition occurs from hydrated/swollen state to 20

dehydrated/collapsed state is referred as lower critical solution temperature (LCST). Therefore, to analyse thermoresponsive behaviour of PNIPAM after being grafted on the surface of MSNs, drug loading and release experiments were performed at 25°C (lower than LCST of PNIPAM) and 40°C (above LCST of PNIPAM).[48][49] For control-MSNs as well as PNIPAM-COOH-MSNs and PNIPAM-Ph-MSNs, doxorubicin was selected for loading and release experiments. The drug loading was performed at 25°C and 40°C and release at 20°C, 30°C and 40°C. The choice of maintaining at these temperatures are due to the thermoresponsive behaviour of PNIPAM chains which will be in open state (swollen state) below 32°C and in a closed state (collapsed state) above 32°C. Observing such temperature responsive behaviour for PNIPAM, it is expected that the drug will be encapsulated below 32°C and will also be released below 32°C, therefore, loading of doxorubicin was performed at 25°C and 40°C, while the release of doxorubicin was performed at 20°C, 30° and 40°C After doxorubicin loading, MSNs were analysed using confocal laser scanning microscopy. As shown in Figure S15 (Supporting Information) and Figure 10, doxorubicin was actively retained in the PNIPAM-Ph-MSNs and PNIPAM-COOH-MSNs observed by the red fluorescence when loading was performed at 25°C. The lack of red fluorescence after 24h at 40°C describes very low loading of doxorubicin inside the pores of PNIPAM grafted MSNs due to collapsed state of PNIPAM chains. The doxorubicin loaded control-MSNs at 25°C and 40°C is shown in Figure S14 in the Supporting Information.

Figure 9. Loading efficiency for (a) PNIPAM-COOH-MSNs and (b) PNIPAM-Ph-MSNs at 25°C and 40°C for 24h; release efficiency for (a) PNIPAM-COOH-MSNs and (b) PNIPAM-Ph-MSNs at 20°C, 30°C and 40°C at different time interval.

21

Efficient drug delivery systems with immense loading and release capacity of molecules is always a crucial parameter. Thus to demonstrate application of PNIPAM grafted MSNs, loading and release studies of doxorubicin were carried out. The detailed loading and release efficiencies are shown in Figure 9 and Table S2 (in the Supporting Information). In the case of PNIPAM-COOH-MSNS, higher loading (61.4%) at 25°C as well as release (54.0%) at 20°C after 24h of doxorubicin was observed as compared to PNIPAM-Ph-MSNs. It gives a coherent idea that as the polymeric chains are mostly on the outer surface of the MSNs for PNIPAM-COOH-MSNs, it allows more amount of doxorubicin to get inside pores of the MSNs. Relatively lower loading (48.8%) at 25°C and release (33.5%) at 20°C after 24h for PNIPAM-Ph-MSNs suggests the polymeric chains to be present more on inside of pores which in turn does not allows the drug molecule to fill-up pores of MSNs. At 25°C, PNIPAM chains are in swollen state which allows doxorubicin to go inside the pores of MSNs as well as exit pores. For better understanding about the release behaviour of doxorubicin from MSNs below LCST temperature of PNIPAM, cumulative release study was performed at different time interval (5, 10, 15 and 24 h) at 20°C. As shown in Figure 9, the release pattern reveals that the release rates depend virtuously upon the temperature at which the release study was performed.

22

Figure 10. Confocal laser scanning micrographs of PNIPAM-COOH-MSNs loaded with doxorubicin at 25°C and 40°C (a) dark field image, (b) in-focus bright field image (c) maximum intensity DIC image.

PNIPAM grafted MSNs are extensively used for drug and antimicrobial loading/release studies on different types of cell lines and bacterial cultures. The deswelling/swelling of PNIPAM (when heated above 32°C or cooled below 32°C) is the dominating factor that modulates the utilization of this polymer for loading as well as release investigations. For example, Fusarium oxysporum[50] is one of the psychotrophs (bacteria) showing higher growth only in temperature range of 24°C to 26°C and can be found in dairy related products and fruits packaging. Targeting such types of organism using PNIPAM grafted MSNs can be one of the foremost application that can be studied further. The swollen state PNIPAM at temperature 25°C or lower will not only allow the antimicrobial agents to load inside the MSNs but will simultaneously permit a virtuous release of the antimicrobial agent in turn destroying the extension of these psychotrophs.

Conclusions In this study, we have successfully demonstrated that by changing the nature of R group present in organoalkoxysilane RAFT agent not only the morphology can be tuned but also location of grafting of polymeric chain can be tuned. The polymer can be selectively grafted either on the interior or exterior surface of the MSNs. This is experimentally achieved via cocondensation in which the R group of the organoalkoxysilane interacts with the hydrophobic hydrocarbon tails of CTAB molecule. Based upon the location of R group of the organoalkoxysilane RAFT agent; MSNs can then be further grafted with PNIPAM via surfaceinitiated RAFT polymerization using grafting-from approach. The appearance of characteristic resonances in 13C and 29Si solid state NMR, vibration bands in FT-IR establishes successful synthesis of organic-inorganic hybrid materials. Appearance of prominent sulphur and nitrogen peaks in XPS for RAFT-COOH-MSNs and PNIPAM-COOH-MSNs confirms that the functional groups are only on the exterior surface of the MSNs. The morphology of the MSNs is thoroughly governed by the nature of the organoalkoxysilane RAFT agent which is

23

remarked from the SEM and TEM. In case of RAFT-COOH-MSNs spherical morphology was obtained while in the case of RAFT-Ph-MSNs cuboid morphology was achieved. Elevated loading as well as release of doxorubicin in case of PNIPAM-COOH-MSNs as compared to PNIPAM-Ph-MSNs also confirms that PNIPAM chains are grafted on the outer and inner surface of MSNs respectively. The concept demonstrated in this manuscript on the preferential grafting of polymers onto the exterior and interior of the mesoporous silica surfaces will potentially lead to the development of advanced materials based on MSNs with application in drug/antimicrobial agent delivery, energy storage, and shear thickening fluids.

Acknowledgements The authors would like to thank National Institute of Plant Genome Research (NIPGR) for access to confocal laser scanning microscope. We thank the Mark Wainwright Analytical Centre, UNSW, for access to solid state NMR spectrometers.

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29

Imprinting the location of an in-built RAFT agent and selective grafting of polymer chains inside or outside the pores of mesoporous silica nanoparticles Smrutirekha Mishra,a Aditya Rawalb and Leena Nebhani*a Smrutirekha Mishra,a Prof. Leena Nebhani*,a a Department of Materials Science and Engineering, Indian Institute of Technology Delhi, New Delhi-110016, India E-mail: [email protected] Dr. Aditya Rawalb b Mark Wainwright Analytical Centre and School of Chemistry, University of New South Wales, Sydney, NSW, 2052, Australia

Highlights •

Mesoporous silica primed with RAFT agent were synthesized via co-condensation of tetraethoxysilane (TEOS) and organoalkoxysilane RAFT agent. The nature of the R group in organoalkoxysilane based RAFT agent was varied in order to control the preferential location of polymer grafting as well as morphology.

•

RAFT and polymer functionalized MSNs were characterized using variety of techniques such as FT-IR, TGA, UV-Visible spectroscopy, surface area measurement, X-ray photoelectron spectroscopy (XPS), 13C and 29Si solid-state NMR spectroscopy.

•

Analysis of thermoresponsiveness of PNIPAM grafted MSNs was experimented by drug loading and release studies at different temperatures.

Imprinting the location of an in-built RAFT agent and selective grafting of polymer chains inside or outside the pores of mesoporous silica nanoparticles Smrutirekha Mishra,a Aditya Rawalb and Leena Nebhani*a Smrutirekha Mishra,a Prof. Leena Nebhani*a a Department of Materials Science and Engineering, Indian Institute of Technology Delhi, New Delhi-110016, India E-mail: [email protected] Dr. Aditya Rawalb b Mark Wainwright Analytical Centre and School of Chemistry, University of New South Wales, Sydney, NSW, 2052, Australia

Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.